Category Archives: Clinical Pearls

Has subclinical hypothyroidism which is being treated with levothyroxine (?link to refractory hypertension)

Hypothyroidism:

Primary hypothyroidism is characterized by a high serum thyroid-stimulating hormone (TSH) concentration and a low serum free thyroxine (T4) concentration

Subclinical hypothyroidism is defined biochemically as a normal free T4 concentration in the presence of an elevated TSH concentration. Secondary (central) hypothyroidism is characterized by a low serum T4 concentration and a serum TSH concentration that is not appropriately elevated

Presence of high serum concentrations of abs to thyroid peroxidase (TPO) and thyroglobulin

Do not routinely measure TPO abs in patients with primary overt hypothyroidism because almost all have chronic autoimmune thyroiditis – can be measured in subclinical hypothyroidism to predict likelihood of progression to permanent overt hypothyroidism

Secondary hypothyroidism: <1 %

TSH deficiency

Pituitary necrosis (eg. Sheehan’s syndrome), trauma, pituitary tumors

Treat with Thyrotropin (TSH, Thyrogen). Usually also need to replace other pituitary hormones.

Treat with Protirelin (TRH, Relefact TRH). Usually also need to replace other pituitary hormones.

In hypothyroidism caused by hypothalamic or pituitary disease, TSH secretion does not increase appropriately as T4 secretion falls. As a result, the symptoms and the serum free T4 value must be used to make the diagnosis. Thus, we measure both serum TSH and free T4 if pituitary or hypothalamic disease is suspected (eg, a young woman with amenorrhea and fatigue)

The clearance of many drugs, including antiepileptic, anticoagulant, hypnotic and opioid drugs, is decreased in hypothyroidism. Thus, drug toxicity may occur if drug dose is not reduced. In addition, drugs that are administered at effective doses in patients who are hypothyroid may become less effective during T4 replacement.

data linking subclinical hypothyroidism with atherosclerosis and myocardial infarction and the increased risk of progression to overt hypothyroidism

supported by ATA, AACE, European thyroid association guidelines

TSH 7-9.9 mU/L: treat most under age 65-70 yo d/t association of increased CV mortality in younger patients. ?benefit in older patients and concerns of safety in older pts (↑ risk of exacerbation and induction of angina and CAD)

TSH ULN-6.9mU/L: treat <65 to 70 who have sxs suggestive of hypothyroidism. Consider if high titers of anti-TPO abs, and patients with goiter. For older patients, these levels of TSH may be age-appropriate.

Currently, I have been seeing patients with hypophosphatemia, and for a few, this has been persistent despite ongoing replacement..

Causes of hypophosphatemia:

Acute respiratory alkalosis

Rise in intracellular pH stimulates phosphofructokinase activity which in turn stimulates glycolysis → ↑ in demand for phosphate, which is driven intracellularly to form glycolytic intermediate metabolites

A similar phenomenon is observed with an increase in intracellular pH, which occurs in metabolic alkalosis

Dieticians are able to calculate patients’ metabolic needs and assess if the feeds are sufficient in meeting this. Had a patient with status epilepticus with persistently low phosphate levels despite frequent replacement. Dietician calculated her needs and found that it significantly exceeded her feeds. After replacing feeds (and also accounting for the fact that patient is on propofol), phosphate levels were generally WNL

Deletions in region of BP1 to BP3 can be subclassified into class I and II deletions

Class I are larger and extend from BP1-BP3 ∴ greater disease severity with need for more seizure medications, greater difficulties in expressive language and higher incidence of autism spectrum disorders

Characteristics:

Severe to profound intellectual disability

Postnatal microcephaly

Movement or balance disorder, usually in the form of gait ataxia and/or tremulous movement of limbs

all participants that are randomized must be included in the final analysis and analyzed according to the treatment group to which they were originally assigned, regardless of the treatment received, withdrawals, loss to f/u or cross-overs

However…in many instances in randomized trials the term intention-to-treat was inappropriately described and participants improperly excluded.

Generally preferred as they are unbiased, and also because they address a more pragmatic and clinically relevant question.

Principles

Keep participants in the intervention groups to which they were randomized, regardless of the intervention they actually received.

Measure outcome data on all participants.

Include all randomized participants in the analysis.

There is no clear consensus on whether all criteria should be applied (Hollis 1999). While the first is widely agreed, the second is often impossible and the third is contentious, since to include participants whose outcomes are unknown (mainly through loss to follow-up) involves imputing (‘filling-in’) the missing data.

E.g. patient receives at least 1 dose of medication and 1 efficacy measurement…as long as that happens they were included in that study

Also consider the number that was censored

More likely to report post-randomization exclusion and more likely to be associated with industry sponsorship

As-Treated: subjects analyzed according to whether they got treatment or not (regardless of allocation) → May be used for safety events

Sensitivity analysis: a repeat of the primary analysis or meta-analysis, substituting alternative decisions or ranges of values for decisions that were arbitrary or unclear

Asks the question: “Are the findings robust to the decisions made in the process of obtaining them?”

For dichotomous outcomes, should odds ratios, risk ratios or risk differences be used?

And for continuous outcomes, where several scales have assessed the same dimension, should results be analysed as a standardized mean difference across all scales or as mean differences individually for each scale?

Different from subgroup analysis:
I. sensitivity analyses do not attempt to estimate the effect of the intervention in the group of studies removed from the analysis, whereas in subgroup analyses, estimates are produced for each subgroup.
II. in sensitivity analyses, informal comparisons are made between different ways of estimating the same thing, whereas in subgroup analyses, formal statistical comparisons are made across the subgroups.

Intention to Treat and Per Protocol

Intention to Treat

Per Protocol

All subjects who were randomized are analyzed at the end of the trial according to the treatment to which they were originally assigned

Included if dropped out

Included if non-compliant (with treatment or following up monitoring)

Included in original group even if treatment changed

This does not fix problems related to loss to f/u

Superiority studies: Conservative
– since the groups are made more artificially similar = makes it harder to show a difference
– minimizes risk of Type I error

Non-inferiority studies: Less conservative
– “is the drug non-inferior = no different than the other”
– difference will not be as visible

All subjects are included only if they received the intended intervention in accordance with the protocol
= ideal patients

Excluded if dropped out

Excluded if non-compliant (with treatment or follow-up monitoring)

Analyzed in new group if treatment changed

Does not test for practical benefit of an intervention

Superiority studies: less conservative
– if there is a benefit, it would be the most visible difference